Deciphering mechanisms of Listeria placental-fetal invasion

项目摘要 单核细胞增生性李斯特菌(Lm)是一种兼性革兰氏阳性胞内细菌，可引起 通过摄入受污染的食物而感染人类。严重感染可发生在老年人和 免疫受损的患者以及孕妇和新生儿也是如此。感染可导致 脑膜炎、脑膜脑炎、脑脓肿，对于孕妇来说，还有流产、死产和 播散性胎儿感染。尽管有抗生素，侵袭性LM病的死亡率很高 治疗突显了管理LM感染的新的有效治疗策略的必要性。 先前的研究表明，不同的LM分离株可以表现出不同的组织趋向性，从而导致 在获得新的靶器官复制利基方面。临床分离到一株LM，07PF0776 根据心脏组织中存在的氨基酸变化，增强靶向心脏组织的能力 InlB，一种与宿主细胞入侵相关的细菌表面蛋白。这些氨基酸的变化 似乎增加了稳定性并促进了与宿主表面硫酸肝素部分的结合，这 结果In1B在宿主细胞表面的募集和对Met的刺激，该受体与 InlB。甲硫氨酸受体在胎盘组织中大量表达，是胚胎和胚胎发育所必需的。 胎盘发育。初步数据显示，至少有两株LM向心性菌株表达了 In1B变种表现出显著增强的垂直传播。我们假设这一修改 InlB可通过操控Met扩大Lm的组织谱系，增强侵袭能力 信号通路，导致胎儿传播率增加。这项建议的具体目的 将对Lm InlB变异株进行功能评估，以检查它们对垂直 以及确定过度表达和/或增加稳定性的机制 增加了垂直传输。目标1将对心脏变力功能进行评估 用于垂直传播效率的菌株，以定义和鉴定构成 增加患胎儿疾病的风险。目标2将确定过度表达的机制 In1B增加了Lm垂直传输。因此，这些研究将阐明精选的LM分离物如何获得 高效接触胎盘/胎儿组织以导致破坏性的新生儿疾病 和死亡。

Project Summary Listeria monocytogenes (Lm) is a facultative gram-positive intracellular bacterium that causes infection in humans via ingestion of contaminated food. Severe infection can occur in elderly and immunocompromised patients well as in pregnant women and neonates. Infection can lead to meningitis, meningoencephalitis, brain abscess, and, for pregnant women, abortion, still-birth, and disseminated fetal infection. The high mortality rate of invasive Lm disease despite antibiotic treatment highlights the need for new effective therapeutic strategies for managing Lm infections. Previous studies have shown that distinct isolates of Lm can exhibit different tissue tropisms, resulting in the acquisition of novel target organ replication niches. A clinical Lm isolate, 07PF0776, was found to have an enhanced ability to target cardiac tissue based on amino acid variations present within InlB, a bacterial surface protein associated with host cell invasion. These amino acid variations appear to increase stability and promote binding to host surface heparin sulfate moieties, which results in recruitment of InlB to the host cell surface and stimulation of Met, the receptor bound by InlB. The Met receptor is abundantly expressed by placental tissue and is required for embryonic and placental development. Preliminary data has shown at least two Lm cardiotropic strains expressing the InlB variant exhibit significantly enhanced vertical transmission. We hypothesize that modification of InlB can expand the tissue repertoire of Lm and enhance invasion through the manipulation of Met signaling pathways, leading to increased rates of fetal transmission. The specific aims of this proposal will undertake a functional assessment of Lm InlB variant strains to examine their efficacy of vertical transmission as well as determine the mechanisms by which overexpression and/or increased stability of InlB increases vertical transmission. Aim 1 will undertake a functional assessment of cardiotropic strains for efficiency of vertical transmission to define and identify strains of Lm that pose an enhanced risk for fetal disease. Aim 2 will determine the mechanisms by which overexpression of InlB increases Lm vertical transmission. These studies will thus clarify how select Lm isolates gain access with high efficiency to placental/fetal tissues to cause devastating forms of neonatal disease and death.